RARE DISEASE
Congenital nephrotic syndrome, Finnish type
Congenital nephrotic syndrome, Finnish type
Congenital nephrotic syndrome, Finnish type
Synonyms: Finnish congenital nephrosis
Synonyms: Finnish congenital nephrosis
Synonyms: Finnish congenital nephrosis
Drug discovery
0
drugs
With orphan designations
Overview
Congenital Nephrotic Syndrome, Finnish Type (CNF) is an autosomal recessive disorder caused by NPHS1 mutations disrupting nephrin, a critical podocyte protein. It manifests prenatally or within 3 months of life with severe proteinuria, hypoalbuminemia, edema, and complications like infections/thrombosis. Progression to end-stage kidney disease (ESKD) typically occurs by age 2–3 years. Diagnosis hinges on genetic testing, as immunosuppressants are ineffective. Management focuses on supportive care and renal transplantation [1][2][6][11].
Burden
High morbidity: Early ESKD, growth failure, thromboembolic events, and life-threatening infections [1][6][12].
Economic strain: Prolonged hospitalizations, albumin replacement, and dialysis/transplant costs [3][6][17].
Mortality: Historically fatal in infancy; modern strategies improve survival but require lifelong renal replacement therapy [1][16].
Therapies
Supportive care: Albumin infusions, RAS inhibitors (e.g., ACEi/ARBs), NSAIDs (indomethacin), anticoagulation, and thyroid supplementation [1][3][17].
Nephrectomy: Reduces proteinuria in refractory cases; bilateral nephrectomy precedes dialysis/transplant [9][17].
Transplantation: Definitive treatment with >90% 5-year graft survival; recurrence risk in Fin-major homozygotes [1][11][17].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
128 drug discovery papers about Congenital nephrotic syndrome, Finnish type, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
128 drug discovery papers about Congenital nephrotic syndrome, Finnish type, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-11-16 | Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome.
Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.
2025-05-03 | Transgenic human nephrin in Drosophila nephrocytes facilitates variant analysis.
Nephrin, the key structural protein of the slit diaphragm, is encoded by NPHS1. Pathogenic variants in this gene are the primary cause of congenital nephrotic syndrome. About 400 variants have been described but functional characterization in vitro is very limited. Here, we express human nephrin in Drosophila nephrocytes, which possess a molecularly conserved slit diaphragm to facilitate functional studies. Immunofluorescence of the human transgene revealed assembly into a complex linear architecture after silencing of sns, the Drosophila nephrin. This pattern suggests lateral clustering of human nephrin into a macromolecular configuration which resembles nephrin in vivo but is absent in cultured cells. In Drosophila nephrocytes, transgenic nephrin colocalized with the endogenous slit diaphragm proteins Pyd and Kirre, indicating a hybrid multi-protein complex. Transmission electron microscopy with pre-embedding immunogold labeling revealed an atypical, tubular ultrastructure. The linear nephrin did not adequately restore membrane invaginations, endocytic function or cellular survival, suggesting that proper signaling function requires additional indispensable cofactors. Murine NEPH1 alone was insufficient but associated with transgenic nephrin. Notably, the linear nephrin assembly provided a read-out for investigation of patient-derived variants. This distinct pattern was altered in transgenes reflecting patient variants with milder clinical presentation, including novel variant NPHS1-V1241G. The impact on the pattern largely correlated with the age of onset of nephrotic syndrome of the respective variant, as demonstrated by automated image annotation for quantitative evaluation. Our findings demonstrate that transgenesis of NPHS1 in nephrocytes is a viable approach for investigation of slit diaphragm formation and precise functional characterization of patient variants.
2024-10-01 | Establishment of a High-Throughput Screening System for Membrane Expression of Mutant Nephrin
Background: Congenital Nephrotic syndrome of the Finnish type (CNF) is caused by a mutation in the NPHS1 gene that hinders the cell surface expression of nephrin and disrupts slit membrane formation. In this study, we constructed a novel evaluation system to search for compounds promoting the expression of nephrin on the cell membrane. Methods: To detect the membrane-expressed nephrin, we used the HiBiT nanoluciferase system by tagging Nephrin wild-type (wt) and mutants (mt) with HiBiT. For high throughput screening (HTS), we generated stable expression cell lines of HiBiT- wt and mutant nephrin (HiBiT-Neph) using the Flp-InTM System. Phosphorylated-Nephrin, which indicates the ability to be translocated to the surface, was also assessed by immunoblotting. Results: In contrast to wt HiBiT-Neph, most mutants did not produce luminescence and were not phosphorylated. Furthermore, among the mutants, we confirmed that the reduction of HiBiT activity in the S366R and E725D stable mutant cells met the HTS criteria. Using E725D stable cells, we screened several chemical chaperones and a natural products compound library. Chemical chaperone β-alanine, a CFTR corrector (Corr-4a), and 78 compounds from the library increased the HiBiT-Neph E725D. Cytotoxicity assays and further validation by immunoblotting of phosphorylated nephrin trimmed the candidate compounds to ten. Focusing on these compounds, we revealed their effects on post-translational modifications and degradation rates of Nephrin to promote the expression of nephrin mutants on the membrane. Conclusion: The HTS evaluation system identified compounds that increased mutant nephrin phosphorylation and cell surface expression and showed that this evaluation system is useful as a drug discovery platform for CNF. Moreover, the identified compounds help to elucidate the mechanisms of mutant nephrin cell regulation.
2025-11-16 | Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome.
Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.
2025-05-03 | Transgenic human nephrin in Drosophila nephrocytes facilitates variant analysis.
Nephrin, the key structural protein of the slit diaphragm, is encoded by NPHS1. Pathogenic variants in this gene are the primary cause of congenital nephrotic syndrome. About 400 variants have been described but functional characterization in vitro is very limited. Here, we express human nephrin in Drosophila nephrocytes, which possess a molecularly conserved slit diaphragm to facilitate functional studies. Immunofluorescence of the human transgene revealed assembly into a complex linear architecture after silencing of sns, the Drosophila nephrin. This pattern suggests lateral clustering of human nephrin into a macromolecular configuration which resembles nephrin in vivo but is absent in cultured cells. In Drosophila nephrocytes, transgenic nephrin colocalized with the endogenous slit diaphragm proteins Pyd and Kirre, indicating a hybrid multi-protein complex. Transmission electron microscopy with pre-embedding immunogold labeling revealed an atypical, tubular ultrastructure. The linear nephrin did not adequately restore membrane invaginations, endocytic function or cellular survival, suggesting that proper signaling function requires additional indispensable cofactors. Murine NEPH1 alone was insufficient but associated with transgenic nephrin. Notably, the linear nephrin assembly provided a read-out for investigation of patient-derived variants. This distinct pattern was altered in transgenes reflecting patient variants with milder clinical presentation, including novel variant NPHS1-V1241G. The impact on the pattern largely correlated with the age of onset of nephrotic syndrome of the respective variant, as demonstrated by automated image annotation for quantitative evaluation. Our findings demonstrate that transgenesis of NPHS1 in nephrocytes is a viable approach for investigation of slit diaphragm formation and precise functional characterization of patient variants.
2024-10-01 | Establishment of a High-Throughput Screening System for Membrane Expression of Mutant Nephrin
Background: Congenital Nephrotic syndrome of the Finnish type (CNF) is caused by a mutation in the NPHS1 gene that hinders the cell surface expression of nephrin and disrupts slit membrane formation. In this study, we constructed a novel evaluation system to search for compounds promoting the expression of nephrin on the cell membrane. Methods: To detect the membrane-expressed nephrin, we used the HiBiT nanoluciferase system by tagging Nephrin wild-type (wt) and mutants (mt) with HiBiT. For high throughput screening (HTS), we generated stable expression cell lines of HiBiT- wt and mutant nephrin (HiBiT-Neph) using the Flp-InTM System. Phosphorylated-Nephrin, which indicates the ability to be translocated to the surface, was also assessed by immunoblotting. Results: In contrast to wt HiBiT-Neph, most mutants did not produce luminescence and were not phosphorylated. Furthermore, among the mutants, we confirmed that the reduction of HiBiT activity in the S366R and E725D stable mutant cells met the HTS criteria. Using E725D stable cells, we screened several chemical chaperones and a natural products compound library. Chemical chaperone β-alanine, a CFTR corrector (Corr-4a), and 78 compounds from the library increased the HiBiT-Neph E725D. Cytotoxicity assays and further validation by immunoblotting of phosphorylated nephrin trimmed the candidate compounds to ten. Focusing on these compounds, we revealed their effects on post-translational modifications and degradation rates of Nephrin to promote the expression of nephrin mutants on the membrane. Conclusion: The HTS evaluation system identified compounds that increased mutant nephrin phosphorylation and cell surface expression and showed that this evaluation system is useful as a drug discovery platform for CNF. Moreover, the identified compounds help to elucidate the mechanisms of mutant nephrin cell regulation.
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